Current Opinion in Hematology最新文献

Purpose of review: Aging is associated with impaired B lymphopoiesis and T lymphopoiesis, contributing to immunosenescence and poor immune recovery. Although this decline can be attributed to intrinsic hematopoietic stem cell aging, growing evidence indicates that lymphoid failure reflects constraints operating across multiple levels of the hematopoietic system. This review frames age-associated lymphopoiesis decline as a systems-level problem and outlines conceptual avenues for therapeutic intervention.

Recent findings: Age-associated lymphoid failure is increasingly attributed to inflammatory suppression, dominance of dysfunctional stem and progenitor states, and compromised extramedullary support. These insights provide a framework for interventions that restore immune competence by rebalancing hematopoiesis or selectively replacing compromised stem cell function.

Summary: Age-associated lymphoid decline arises from coordinated constraints across the bone marrow niche, stem and progenitor composition, and extramedullary lymphoid support, rather than intrinsic stem cell exhaustion alone. Targeting these bottlenecks in a context-dependent manner offers multiple routes to improve lymphopoiesis and restore immune competence in aging.

Purpose of review: BEACH-domain-containing proteins (BDCPs) are large scaffolding proteins that regulate vesicle trafficking, autophagy, and granule biogenesis. This review synthesizes recent mechanistic and clinical advances defining BDCP functions in hematopoietic stem and progenitor cell (HSPC) biology, immune regulation, and platelet function, highlighting relevance to human disease.

Recent findings: Although BDCPs were initially linked to lineage-restricted hematopoietic disorders such as Chediak-Higashi syndrome and Gray platelet syndrome (GPS), emerging evidence demonstrates broader roles for BDCPs including NBEA, LRBA, LYST, and NBEAL2 in HSPC maintenance, receptor trafficking, and lineage specification. NBEA regulates NOTCH receptor turnover in HSPCs, linking vesicle dynamics to stem cell fate decisions. Recent studies provide mechanistic insights on how LRBA controls autophagy and CTLA-4 recycling, informing abatacept therapy; how NBEAL2 governs platelet α-granule biogenesis and immune homeostasis in GPS; and how LYST regulates lysosomal size and granule maturation in myeloid cells. Additionally, WDFY3, WDFY4, and WDR81 emerge as regulators of autophagy, antigen presentation, and inflammatory signaling.

Summary: Collectively, BDCPs integrate vesicle trafficking, autophagy, and receptor homeostasis to coordinate hematopoietic development and immune function. Their dysfunction underlies immunological, hematologic, and inflammatory disorders, positioning BDCPs as promising translational targets.

Purpose of review: This review summarizes current understanding of platelet-endothelial contributions to thrombosis, emphasizing molecular crosstalk [von Willebrand factor (VWF)/ADAMTS13 balance, P-selectin, platelet glycoprotein VI (GPVI), integrins, extracellular vesicles, neutrophil extracellular traps (NETs)], high-risk clinical settings, and translational advances. Highlighting GPVI-directed therapeutics, the VWF/ADAMTS13 axis in COVID-19, and opportunities and challenges for targeting the platelet-endothelial interface.

Recent findings: Clinical and translational studies support the safety and potential efficacy of targeting platelet-endothelial interfaces. GPVI inhibitors (Glenzocimab, Revacept) have advanced through phase I/II studies with reassuring bleeding profiles and suggest benefit in ischemic stroke and lesion-directed settings. Direct interruption of platelet-VWF interactions (Caplacizumab) is established in immune thrombotic thrombocytopenic purpura (TTP), while studies show a persistent VWF/ADAMTS13 imbalance in severe COVID-19 and inflammatory states linked to microthrombosis and worse outcomes. Antiadhesion strategies (P-selectin blockade) and modulators of immunothrombosis (NET inhibitors, targeting extracellular vesicle) are also in evaluation.

Summary: Targeting platelet-endothelial crosstalk has potential to reduce pathologic thrombosis while preserving hemostasis. Clinical proof of principle exists for focused approaches (anti-VWF in TTP; P-selectin blockade in vaso-occlusion; emerging GPVI inhibitors). Priorities are: defining disease contexts and timing where interface targeting is effective; validating biomarkers (VWF/ADAMTS13 ratio, soluble P-selectin, platelet activation signatures) for patient selection; and conducting adequately powered trials with rigorous bleeding endpoints.

Purpose of review: 10-20% of myeloproliferative neoplasms (MPNs) are diagnosed in adolescent and young adult (AYA) patients. This review aims to summarize current literature on AYA MPN, to highlight unique clinico-pathological patterns, specific treatment paradigms and areas for further research.

Recent findings: Epidemiological data highlights the female predominance in AYA MPN, reflective of the higher burden of essential thrombocythemia (ET) within this population. Fatigue is common and can be severe but is frequently overlooked within the healthcare setting. Compared to older MPN, cytopenias are less common and CALR mutations are frequently encountered. Interferon is the preferred first-line agent in AYA MPN and holds potential for disease modification. Clinicians should be mindful of the unique challenges facing AYA patients including professional demands, family planning, pregnancy and psychological health when assessing and counselling patients with MPN.

Summary: AYA MPN patients have unique clinico-pathological characteristics that alter their disease presentation, thrombo-haemorrhagic risks and kinetics of progression. Further research should focus on developing AYA-specific risk stratification models, the impact of nondriver somatic mutations, and therapies with potential for disease modification.

Purpose of review: TP53- mutated ( TP53 -MT) myeloid neoplasms (MN) represent one of the most challenging disease subsets due to their distinct pathobiology, frequent association with therapy-related disease, chemo-resistant phenotype, and dismal outcomes. The prognostic impact of TP53 -MT is not uniform and is influenced by disease state, allelic burden, and co-occurring cytogenetic and molecular aberrations that shape disease trajectory. While current prognostic models incorporate TP53 status, they incompletely capture the heterogeneity within TP53 -MT MN. Therapeutic options remain limited, with allogeneic stem cell transplantation being the only intervention offering long-term survival in selected patients.

Recent findings: Novel approaches, including p53 reactivators and anti-CD47 antibodies in combination with standard-of-care therapies, have been explored; however, none has yet transformed the natural history of TP53 -MT MN.

Summary: This review highlights the current understanding of TP53 -MT MN, evolving strategies of prognostic stratification and propose a practical framework for clinical management. We further discuss the critical unmet need for collaborative, biologically informed clinical trials to improve outcomes of this challenging disease entity.

Purpose of review: Myeloproliferative neoplasm-unclassifiable (MPN-U) is a heterogenous subtype of Philadelphia-chromosome negative (Ph-) MPN that comprises 5-20% of Ph- MPN cases. Given the clinical and molecular variability of presentation, there are no clear data regarding risk stratification and management of MPN-U. In this review, we aim to summarize the current evidence regarding MPN-U with regards to diagnosis, risk stratification, and treatment approaches.

Recent findings: Current diagnostic criteria require exclusion of other chronic myeloid malignancies along with identifying the typical pathologic findings of an MPN in order to diagnose MPN-U. While there are not dedicated prognostic scores regarding thrombotic risk and survival specifically for MPN-U, phenotype-agnostic scores may have utility. In addition, the Dynamic International Prognostic Scoring System (DIPSS)+ score has demonstrated that it can identify higher-risk MPN-U. There are no consensus treatment recommendations available for MPN-U.

Summary: When considering management of MPN-U, for patients in the cellular phase, we consider cytoreduction in patients identified as high-risk, for fibrotic-phase disease, we consider JAK inhibition for splenomegaly/constitutional symptoms and allogeneic transplantation for higher-risk patients, and for accelerated/blast-phase disease we employ hypomethylating-agent based approaches with the intent of allogeneic transplant for eligible patients.

Purpose of review: Systemic sclerosis (SSc) is characterized by early and persistent vascular injury, immune dysregulation, and fibrosis, with a growing recognition of an excess thrombotic burden that cannot be fully explained by traditional cardiovascular risk factors. Increasing experimental and clinical evidence positions platelets as mediators at the interface of vasculopathy, inflammation, and coagulation in systemic sclerosis. This review addresses emerging platelet-driven mechanisms that extend platelet function beyond haemostasis and highlight their role as intravascular messengers capable of propagating damage across organs.

Recent findings: Recent literature demonstrates that platelets in SSc exhibit a persistently activated and primed phenotype, driven by endothelial injury, aberrant platelet-collagen interactions, inflammation-mediated priming, and defective platelet clearance. Activated platelets interact dynamically with immune cells, particularly neutrophils, promoting neutrophil extracellular trap formation and immunothrombosis through pathways involving HMGB1, P-selectin-PSGL-1, and GPVI. Platelet-derived mediators, including CXCL4, serotonin, PDGF, and extracellular vesicles, enable the dissemination of inflammatory and profibrotic signals, thereby contributing to endothelial dysfunction, immune activation, and fibrotic remodelling in distant vascular beds. Clinical studies increasingly link platelet activation markers with distinct disease subsets and major organ complications.

Summary: Collectively, these findings identify platelets as key orchestrators and conveyors of immunothrombosis and thromboinflammation in SSc. Improved understanding of platelet-driven signalling networks may inform risk stratification and support the development of targeted antithrombotic or immunomodulatory strategies, although robust evidence for disease-modifying antiplatelet interventions remains limited.

Purpose of review: SARS-CoV-2 disease (COVID-19) is increasingly recognized as a thromboinflammatory vascular disorder characterized by dysregulated complement activation, endothelial injury, and sustained hypercoagulability. This review examines emerging evidence that extracellular vesicles act as key intermediaries linking complement activation to coagulation in acute and postacute COVID-19 infection.

Recent findings: Recent studies demonstrate that extracellular vesicles released from platelets, endothelial cells, and neutrophils are markedly increased in COVID-19 and exhibit a combined procoagulant and complement-active phenotype. Sub-lytic complement attack, particularly membrane attack complex (MAC) deposition, triggers phosphatidylserine exposure and extracellular vesicle shedding, generating vesicles that support thrombin generation and propagate complement activity in the circulation. Extracellular vesicle-associated complement components, including C1q, C3 fragments, MASP2, and preassembled MACs, promote tissue factor decryption, platelet activation, and assembly of the prothrombinase complex, establishing a self-amplifying thromboinflammatory loop. Proteomic profiling further reveals compartment-specific extracellular vesicle signatures, with systemic extracellular vesicles enriched in complement and coagulation pathways. Importantly, complement-bearing and tissue factor-bearing extracellular vesicles persist beyond acute infection and are increasingly implicated in postacute sequelae of COVID-19.

Summary: Extracellular vesicles serve as mobile platforms integrating complement activation with coagulation, providing a mechanistic framework for acute and chronic immunothrombosis in COVID-19. Targeting extracellular vesicle-mediated complement-coagulation crosstalk may offer novel diagnostic and therapeutic opportunities.